tbuckley/cabot-search huggingface dataset:
P20.05.A USE OF VISMODEGIB IN ADULT PATIENTS WITH NEOPLASTIC MENINGITIS FROM SONIC HEDGEHOG (SHH)-ACTIVATED MEDULLOBLASTOMAS: A CASE REPORT
Authors: F Bruno, A Pellerino, R Palmiero, E Pronello, L Bertero, M Levis, R Soffietti, R Rudà
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Vismodegib is a SHH-inhibitor that proved to be effective in locally-recurrent SHH-activated medulloblastoma. However, whether vismodegib is effective in case of neoplastic meningitis (NM) as well has not been assessed so far. Here, we present a case of a patient with NM from SHH-activated medulloblastoma who showed a dramatic response to vismodegib. Case Report: A 34-year-old patient was diagnosed with a SHH-activated cerebellar medulloblastoma in 2015. He underwent gross-total resection, cranio-spinal radiotherapy (RT) and 5 cycles of lomustine, vincristine and cisplatin. Then, he remained disease-free until October 2021, when the MRI showed a new single contrast-enhanced nodule in the spine (T10), which was treated with stereotactic RT. However, the following MRI showed a diffuse leptomeningeal involvement, with new multiple linear and nodular lesions. The CSF cytology confirmed the presence of neoplastic cells. Therefore, in April 2022 vismodegib (150 mg daily) was started. The treatment was well tolerated, except for increased creatine phosphokinase (CTCAE v3.0 grade 1). After only 2 months of therapy, a reduction of the meningeal enhancement was seen on MRI, and after 4 months all nodular and linear lesions disappeared. Similarly, CSF cytology became negative after 4 months of treatment. However, after 8 months of treatment (December 2022), the MRI of the spine showed the new appearance of meningeal contrast-enhanced lesions, and CSF cytology confirmed the presence of neoplastic cells. Therefore, vismodegib was dismissed. In few days, the patient (who did not have any symptoms so far) developed severe meningeal symptoms, and palliative care was started, until his death in February 2023. CONCLUSION To our knowledge, this is the first report of an adult patient with NM from SHH-activated medulloblastoma achieving a complete response with vismodegib, even if temporary. Data from larger series are needed to confirm the effectiveness and safety of vismodegib in case of leptomeningeal spread.
P07.12.A DIAGNOSTIC POTENTIAL OF INFRARED SPECTROSCOPY IN MENINGIOMA PATIENTS
Authors: S Richter, R Galli, M Kirsch, I Eyüpoglu, O Uckermann
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Vibrational spectroscopy probes molecular vibrations in the tissue and can provide optical diagnosis of brain tumors. Here, we investigated its potential for the identification of aggressive meningioma. MATERIAL AND METHODS Tissue samples were obtained during routine surgery from 113 meningioma patients (WHO 1 n= 33; WHO 2 n=39; WHO 3 n=41). Infrared (IR) spectroscopic imaging was performed at three positions (170 x 170 µm, 16x16 = 256 spectra) on frozen sections in reference to HE histology. Spectra were labeled according to the clinical diagnosis of the patient. Baseline correction, area normalization and fourfold spectral binning was performed. Spectra displaying artifacts were identified by visual inspection and were excluded from further analysis. The data was split into test and training set. 42825 spectra of 57 specimens (training set) were utilized to develop an algorithm using linear discriminant analysis to identify aggressive WHO 3 meningioma. RESULTS The developed algorithm assigned 88.6% of the 40626 spectra of the independent test set to the correct class. Based on these RESULTS , the class assignment for each measurement position was calculated as mean of class assignment of the respective spectra: All WHO 1 (16/16) samples, 16/19 WHO 2 and 17/21 WHO 3 meningioma were correctly assigned at all three positions. One sample of meningioma WHO 3 was misclassified at all measurement positions. However, in case of six patients inconclusive results were obtained for the samples as the measurement positions were assigned to different classes. Comparison of IR spectral signatures revealed increased bands at 1114, 1242, 1336 and 1450 cm-1 and decreased bands at 1544 and 1651 and 1734 cm-1 in meningioma WHO 3. This suggests increased phospholipids and decreased proteins as main difference to meningioma WHO 1 and 2 and might form the basis for diagnostic exploitation of IR spectral information. CONCLUSION IR spectroscopy qualifies as reliable tool for the identification of aggressive meningioma. Based on the classification results of this study, translational strategies may be deduced. The data suggests, that analysis of the tumor needs to be performed at multiple sites to obtain reliable clinical information. In case of conflicting results at different measurement positions, the tissue should be evaluated as unratable. As infrared spectroscopy can be applied in situ using fiber based systems, it might allow intraoperative meningioma grading and tumor delineation in future translational settings.
P20.08.B CLINICAL AND MOLECULAR ANALYSES OF A SERIES OF ADULT PILOCYTIC ASTROCYTOMA
Authors: I Manzano-Benito, B Moreno Torres, D Cantero, A Hernández-Laín, Á Romo, Á Rodríguez de Lope, M Mollejo, B Meléndez
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Pilocytic astrocytoma (PA) is a rare, grade 1 subtype of glioma. It is most frequent during the first two decades of life, the incidence rate decreasing with age. PAs are usually located in the cerebellum, although they have also been described in other sites. They are circumscribed, solid-cystic, with low cellularity and generally slow-growing tumours with good prognosis in the paediatric age group. PA is associated with MAPK pathway dysregulation, most often showing BRAF gene alterations. PA is very rare in older adults and is associated in some cases with a worse prognosis. In this work we set out to analyse a series of adult PA from a clinical, morphological and molecular point of view. MATERIAL AND METHODS Clinical data were collected from a group of adult patients diagnosed with PA. Nucleic acid extraction was performed by automated extraction and the samples were analysed through a 30-gene targeted panel for gliomas by using Next-Generation Sequencing. Tandem duplication causing fusion of KIAA1549 and BRAF genes (K-B fusion) was analysed by RT-PCR. RESULTS Thirty-four patients were included, with a mean age of 34.4 years (range, 18-57 years). The male/female ratio was 26/8. Mean overall survival was 150.5 months, with more than 10 years of mean follow-up. At the time of the last review, 91% (30/33) of the patients remained alive, while the remaining 9% (3/33) died. Neuroanatomic locations (31 cases) were as follows: cerebrum/lobar 23% (7), cerebellum 39% (12), brainstem 10% (3), ventricle 6% (2), spinal cord 10% (3), optic nerve 13% (4). The K-B fusion was detected in 44% of cases (8/18). Of these, 87.5% (7/8) and 12.5% (1/8) showed fusions involving exons 16:9 and 15:9, respectively. K-B positive cases had a mean age of 40 years. Analyses by NGS revealed mutations in NF1 (15%), BRAF (11%), PDGFRA (11%), EGFR (7%) and PIK3CA (7%). Other variants observed in 4% of cases involved ATRX, CIC, IDH1, KEL, KRAS, MET, MSH6, PTPN11 and RB1. No alterations were detected in 3 of the cases, suggesting that other untested driver alterations could be present. CONCLUSION In this series, no significant differences with childhood PA in the frequency of molecular alterations were observed, in contrast to other gliomas where there are strong differences in the molecular alterations between adult and paediatric tumours. The most common genetic alterations in adult PA involved the MAPK pathway, as previously reported. In contrast to other adult PA studies, the frequency of K-B fusion was similar to that of paediatric PA. Molecular alterations related to an aggressive behaviour or to other glioma types were identified, such as mutations of ATRX, PDGFRA, NF1 or PI3KCA, which can suggest other tumour types. Our results suggest the need for multilayer histological and molecular diagnosis to appropriately manage adult PA.
P10.13.A AN ATRAUMATIC ACCESS TO HUMAN GLIOBLASTOMA IN A XENOGRAFT ANIMAL MODEL BY CEREBRAL OPEN FLOW MICROPERFUSION FOR THE ASSESSMENT OF BIOMARKER IN THE TUMOR MICROENVIRONMENT
Authors: T Altendorfer-Kroath, M Asslaber, J Hummer, E Zügner, D Schimek, E Prugger, S Stanzer, B Prietl, T R Pieber, E Bernhart, C Magnes, T Birngruber
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Orthotopic xenograft studies strongly promote the development of targeted/personalized cancer therapies to improve the still poor life expectancy of glioblastoma patients. In recent years, the tumor microenvironment has increasingly become subject of investigations, as it could have an impact on the progression of the cancer. However, examination of the tumor microenvironment with currently available methods inevitably causes trauma that might compromise the reliability of the obtained data. We aimed to implement an atraumatic access to human glioblastoma with cerebral Open Flow Microperfusion (cOFM) by implantation of xenograft cells in rodent’s brain of different species (mouse and rat) with intact blood brain barrier (BBB) and subsequent development of a xenograft glioblastoma at the interface between the cOFM probe and the surrounding brain tissue. Thereafter, we used the cOFM probe to collect interstitial fluid (ISF) from the tumor microenvironment for metabolome and biomarker assessment. MATERIAL AND METHODS Human glioma cells were implanted at a well-defined position into immune-deficient rodent’s brain via cOFM or syringe. Characteristics of the mature tumors from both groups were assessed. ISF from tumor microenvironment was collected without further traumatization by using cOFM, and the collected tumor ISF samples were analyzed using a UHPLC-HRMS metabolomics platform. A targeted (Biocrates MxP®) and an untargeted (Metaboanalyst) approach were used to analyze the metabolomics data. RESULTS For the first time xenograft cells were successfully introduced into rodent brain with intact BBB using cOFM, and the tumor tissue that developed around the cOFM probe was unaffected by the presence of the probe. Thereby, an atraumatic access to the tumor was created. The mature cOFM-induced tumors resembled the syringe-induced ones and showed typical features of human glioblastoma. The cOFM sampling procedure did not alter tumor morphology. CONCLUSION This novel atraumatic access to human glioblastoma in a rodent brain was used to collect ISF from functional tumor microenvironment in vivo without trauma generation. The thereby generated reliable data are likely to promote drug research, biomarker identification, and enable investigation of the BBB of a functional tumor.
P02.14.B SPATIAL TRANSCRIPTOMIC ARCHITECTURE OF TUMOURS OF THE PERIPHERAL NERVOUS SYSTEM
Authors: P Heiland, J A Menstell, O Schnell, J Beck, J Bremer, D Heiland
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Studies into the genetics of peripheral nerve tumors have been focused on their association with known gene mutations and syndromes as well as on the tumor microenvironment of malignant peripheral nerve sheath tumors. Still, not many advances have been made into clarifying the structure and diverse pathophysiology of these tumors. Here we present spatially resolved transcriptomic profiling of benign and malignant entities and describe the topographical architecture of the neoplastic and microenvironmental diversity. MATERIAL AND METHODS We employed spatially resolved transcriptomics using the 10X Visium technology from paraffine embedded specimens. We included hybrid peripheral nerve sheath tumors (HPNSTs) plexiform neurofibromas and malignant peripheral nerve sheath tumors (MPNST). Computational analysis was employed by the SPATA2 toolbox. Transcriptomic niches were identified by graph-based spatial clustering. Correlation of histomorphological features and transcriptomic programs was performed by a co-expression network-based analysis. RESULTS We identified hub genes associated with neurofibroma and schwannoma histopathology across primary pathologies and discovered that neurofibroma regions of HPNSTs exhibited unique transcriptional programs marked by a significant higher local accumulation of bone-derived macrophages and lymphoid cells compared to primary neurofibromas. A novel marker, Apolipoprotein D (APOD), was found to accurately identify neurofibroma subregions in HPNSTs, which was confirmed by immunostaining in a control cohort. In MPNSTs, we observed a high grade of inter- and intrapatient heterogeneity driven by unique transcriptional niches and genetic variability. Subsequent pathway analysis revealed distinct oncogenic signaling driver across regional niches along with variance in immune infiltration. Our findings highlight the disbalance between histological annotation and actual tumor cell abundance in MPNSTs indicated by inferred copy number alterations. CONCLUSION Our integrated analysis pipeline revealed distinct transcriptional signatures and cellular interactions within benign PNSTs, including neurofibromas and hybrid peripheral nerve sheath tumors (HPNSTs) and sought to expose the tumor heterogeneity of MPNST and identify various cancer niches. Our study underscores the potential of spatially resolved transcriptomics as a powerful tool for advancing our understanding of PNST biology, and ultimately improving diagnosis, prognosis, and treatment strategies.
P06.05.A INTRACEREBROVENTRICULAR TCR-TRANSGENIC T CELL THERAPY TO TREAT GLIOBLASTOMA (INVENT4GB)
Authors: L Bunse, M Kratzmann, Y Chih, K Sanghvi, A de Roia, R Harbottle, S Eichmüller, A Benner, E Green, I Poschke, P Schmidt, J Steinbach, P Vajkoczy, L Bullinger, G Tabatabai, M Stenzinger, H Bönig, W Wick, M Platten
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Novel concepts in immunotherapy have evolved with the identification of potential (neo)epitopes and/or combinations with immune checkpoint inhibitors (ICI). In contrast to many other solid tumors, ICI have not improved outcome for patients with glioblastoma (GB) in phase 3 studies. However, antigen-specific T cells induced by vaccines or adoptively transferred as chimeric antigen receptor (CAR) T cells produced encouraging responses in early clinical trials and case series. From one of these trials, the Actively Personalized Vaccine Consortium (GAPVAC) European Clinical Trial 101, we have identified a human leukocyte antigen (HLA)-A2-restricted T cell receptor (TCR) targeting protein tyrosine phosphatase receptor type zeta 1 (PTPRZ1). PTPRZ1 is strongly overexpressed in malignant gliomas, especially GB, and analyses of intratumoral heterogeneity revealed that the level of PTPRZ1 overexpression is strongly associated with cancer stemness. The PTPRZ1 epitope is naturally presented on HLA-A2. MATERIAL AND METHODS INVENT4GB is a German, multicenter, phase 1, first-in-human, first-of-kind dose-escalation window-of-opportunity investigator-initiated trial in recurrent GB, eligible for re-resection, assessing safety and feasibility of therapy with intravenously (iv) and intraventricularly (icv) infused TCR-engineered T cells (TCR-T). FPI is scheduled for 2024. HLA-A*02:01 positive patients will receive one neoadjuvant iv followed by up to three adjuvant icv infusions of PTPRZ1-specific TCR-transgenic autologous T cell therapy (TCR-T-001) with cyclophosphamide- and fludarabine-based lymphodepletion prior to iv infusion. Patient autologous T cells will be engineered by non-integrating nano scaffold matrix attachment region (SMAR) TCR DNA vectors. Icv infusions will be performed via intraventricular catheter implanted during re-resection. Biomarker discovery includes magnetic resonance imaging (MRI) and longitudinal flow cytometry-based immune monitoring of blood and cerebrospinal fluid. Primary endpoints are feasibility and safety (determination of maximum tolerated dose/ MTD), key secondary endpoints are progression-free survival according to the Immunotherapy Response Assessment in Neurooncology (iRANO) criteria. RESULTS TCR-T-001 robustly recognizes target-expressing cells in vitro and is efficacious in preclinical tumor models. Preclinical data and the trial concept will be presented. CONCLUSION INVENT4GB is a first-of-kind TCR-engineered T cell therapy for GB patients.
P10.21.A THE ABCB1/ABCG2 INHIBITOR ELACRIDAR IS A MORE POTENT PHARMACOENHANCER COMPARED TO TARIQUIDAR FOR TREATMENT OF INTRACRANIAL TUMORS WITH SMALL MOLECULE DRUGS
Authors: A Lentzas, M C de Gooijer, S Zuidema, C H Çitirikkaya, N Venekamp, J H Beijnen, O van Tellingen
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND The blood-brain barrier (BBB) is a major hurdle to successful pharmacotherapy of brain tumors. ABCB1 and ABCG2 are efflux transporters that are expressed in brain tumor vessels and reduce the uptake of many small molecule drugs. Elacridar and tariquidar are both dual ABCB1 and ABCG2 inhibitors. We aim to improve pharmacotherapy of brain cancer by concomitant use of potentially effective drugs with elacridar. Since tariquidar has mostly been used to assess the effects of ABC-transporters on brain uptake in human studies with PET tracers, we decided to compare both agents in our rodent models. MATERIAL AND METHODS We used Abcg2;Abcb1a/b double knockout (DKO), Abcb1a/b KO, Abcg2 KO and wild-type mice receiving a cocktail of 7 model drugs at a fixed low dose in combination with elacridar or tariquidar at a range of doses. Drugs were given by 3-h infusion. DKO mice are the reference for complete inhibition, while single KO mice allow interrogation of the remaining transporter in case of dual substrate drugs. Brain and plasma levels were measured by LC-MS/MS. RESULTS Complete inhibition of Abcb1 by elacridar was achieved when the plasma level is about 1.0 μM. However, a much higher plasma level (&amp;gt;4 μM) of tariquidar was needed. Inhibition of Abcg2 was more difficult. For erlotinib and palbociclib about 1.0 μM of elacridar was sufficient, but other more profound Abcg2 substrate drugs never reached the B/P ratios achieved in reference to DKO mice, even at 4 μM. Strikingly, tariquidar could not enhance the brain uptake of ABCG2-subtrate drugs in Abcb1a/b KO mice. The B/P ratio of elacridar in DKO mice was 6. Elacridar improved its own brain distribution in WT mice, achieving steady-state B/P ratios at plasma level above 1.4 μM. The B/P ratio of tariquidar in DKO mice was about 2, while in WT and Abcb1a/b KO mice was 0.3 and did not increase even at plasma concentration &amp;gt;8 μM. Only in Abcg2 KO mice, the B/P ratio increased to levels of DKO mice at tariquidar plasma levels of &amp;gt; 6 μM. CONCLUSION Elacridar is a much more potent inhibitor of Abcb1a/b and Abcg2 at the BBB. Elacridar can act as a pharmaco-enhancer of ABCB1 substrate drugs and weaker ABCG2 substrates. Tariquidar will enhance the brain penetration of ABCB1 substrates, but full inhibition is only achieved at levels above those reported in human subjects. The efflux of tariquidar by Abcg2 at the BBB severely compromises the usefulness of tariquidar as a pharmaco-enhancer for brain delivery.
P18.02.B RELATIONSHIP BETWEEN PROGESTERONE RECEPTOR EXPRESSION WITH HISTOPATHOLOGICAL GRADING IN MENINGIOMA
Authors: D Rahmawati, D Retnani, H Holipah, Y Damayanti
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Meningioma is a group of mostly benign, slow-growing neoplasms that most likely derive from meningothelial cells of the arachnoid layer of the brain and spinal medulla. Meningiomas are found in one-third of all tumors in the central nervous system. Meningioma is three times more prevalent in women than in males, it is frequently related to hormones in women, particularly progesterone, which is considered to have the utmost impact on meningioma. Objective: this study aims at discovering the relationship between progesterone receptor expression and meningioma histopathological grading in Indonesia, especially at Saiful Anwar Hospital Malang. Method: This study employed a cross-sectional analytical observational research design. The study sample was a paraffin block of meningioma cases at The Anatomical Pathology laboratory of Saiful Anwar Hospital and The Medical Faculty of Brawijaya University, obtained from 2017 to 2020. The data were collected through histopathological preparations, immunohistochemical preparations, and immunohistochemical evaluation. The data analysis was performed by using SPSS version 20. RESULTS Most meningioma cases at Dr. Saiful Anwar Malang Hospital are women between 41 and 50 years. Then, it is located in the frontal part and acquired a grade of histopathology I and has a progesterone receptor expression score of 4. The chi-square test showed no significant association between progesterone receptor expression and histopathological grading of meningioma. At the same time, partial logistic regression tests showed no significant association between sex, age, and location with meningioma histopathological grading. In addition, multinomial logistic regression tests showed that the sex, age, and location did not significantly increase or decrease the risk (odds ratio) to the grade of meningioma histopathology. CONCLUSION This study showed no significant association between progesterone receptor expression and meningioma histopathological grading and no association between the sex, age, and location of lesions with meningioma histopathological grading and no significant increased risk of histopathological grading due to gender, age, or lesion location.